The overall goal of the research is to elucidate the role played by several eptidergic hormones in the normal regulation of food intake and body weight in rats. The driving hypothesis is that body weight (or, more specifically, body adiposity) is precisely regulated, and that this regulation depends at least in part upon adiposity-related signals that travel in the blood. There is considerable evidence that the pancreatic hormone insulin is one such signal since its secretion is directly proportional to adiposity and since it gains access to the brain via a receptor-mediated transport system. We have already found that adding insulin in small quantities to the brain causes animals to eat less and lose weight. We are now concentrating upon how insulin, once it enters the brain, interacts with other systems important in the control of food intake. In particular, we will investigate the interaction of central insulin with anorexigenic peptides (cholecystokinin, for example), with orexigenic peptides (e.g., NPY), and with compounds including adrenal steroids which alter the brain's sensitivity to insulin. We will also investigate the brain-insulin system and the intake, of specific dietary macronutrients (fats, carbohydrates and proteins). Finally, we will determine how central insulin influences energy expenditure and body metabolism. These experiments are critical for a complete understanding of the normal controls over weight regulation and may suggest novel therapeutic strategies for eating disorders and/or obesity.